ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.2252-2A>G (rs1131691105)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492705 SCV000581305 likely pathogenic Hereditary cancer-predisposing syndrome 2016-02-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Center for Human Genetics, Inc RCV000660007 SCV000781941 likely pathogenic Neurofibromatosis, type 1 2016-11-01 criteria provided, single submitter clinical testing
Invitae RCV000660007 SCV000826189 pathogenic Neurofibromatosis, type 1 2018-03-05 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 18 of the NF1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with neurofibromatosis, type I and pheochromocytoma (PMID: 17426081). ClinVar contains an entry for this variant (Variation ID: 428984). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. A different variant affecting this nucleotide (c.2252-2A>C) has been determined to be pathogenic (PMID: 12872266). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). For these reasons, this variant has been classified as Pathogenic. comment

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